Leptin promotes proliferation of human undifferentiated spermatogonia by activating the PI3K/AKT/mTOR pathway.

BACKGROUND: Male infertility is a common disease affecting male reproductive health. Leptin is an important hormone that regulates various physiological processes, including reproductive function. However, few experimental studies have been carried out to elucidate the mechanism of leptin's effects on male reproductive function. OBJECTIVE: The purpose of this study was to investigate the effects of leptin on testicular spermatogenesis and its mechanism, so as to provide potential targets for the treatment of patients with spermatogenic dysfunction. METHODS: Testicular tissues were collected from eight prostate cancer patients undergoing surgical castration. GPR125-positive spermatogonia were isolated by two consecutive magnetic activated cell sorting (MACS), followed by incubation with conditioned medium. To identify the signaling pathway(s) involved in the effects of leptin, undifferentiated spermatogonia were treated with different concentrations of leptin and antagonists of leptin-related pathways. The proliferative effect of leptin was evaluated by cell counting using a hemocytometer. Expressions of p-AKT, p-ERK, p-STAT, and p-S6K were determined by western blotting analysis. RESULTS: Leptin promoted the growth of human GPR125-positive spermatogonia in a concentration-dependent manner. The most significant proliferative effect was observed using 100 ng/mL leptin after 6 days of culture. Leptin significantly increased the phosphorylation of STAT3, AKT, and ERK in undifferentiated spermatogonia. Phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 inhibited the leptin-induced activation of AKT, ERK, and downstream S6K. Treatment with the mammalian target of rapamycin (mTOR) inhibitor rapamycin also inhibited S6K phosphorylation. Moreover, both LY294002 and rapamycin were found to inhibit the leptin-induced proliferation of undifferentiated spermatogonia. These results suggested that the leptin-induced proliferation of GPR125-positive spermatogonia was dependent on the PI3K/AKT/mTOR pathway. Further exploration of proliferation and apoptotic markers suggested that leptin may alleviate cell apoptosis by regulating the expression of Bax and FasL. CONCLUSIONS: A certain concentration of leptin (25∼100 ng/mL) could promote proliferation of undifferentiated spermatogonia, which was mediated by PI3K/AKT/mTOR pathway.

Interplay between obesity and aging on myocardial geometry and function: Role of leptin-STAT3-stress signaling.

BACKGROUND: Uncorrected obesity facilitates premature aging and cardiovascular anomalies. This study examined the interaction between obesity and aging on cardiac remodeling and contractile function. METHODS: Cardiac echocardiographic geometry, function, morphology, intracellular Ca2+ handling, oxidative stress (DHE fluorescence), STAT3 and stress signaling were evaluated in young (3-mo) and old (12- and 18-mo) lean and leptin deficient ob/ob obese mice. Cardiomyocytes from young and old lean and ob/ob mice were treated with leptin (1 nM) for 4 h in vitro prior to assessment of mechanical and biochemical properties. High fat diet (45% calorie from fat) and the leptin receptor mutant db/db obese mice at young and old age were evaluated for comparison. RESULTS: Our results displayed reduced survival in ob/ob mice. Obesity but less likely older age dampened echocardiographic, geometric, cardiomyocyte function and intracellular Ca2+ properties, elevated O2- and p47phox NADPH oxidase levels with a more pronounced geometric change at older age. Immunoblot analysis revealed elevated p47phox NADPH oxidase and dampened phosphorylation of STAT3, with a more pronounced response in old ob/ob mice, the effects were restored by leptin. Obesity and aging inhibited phosphorylation of Akt, eNOS, AMPK, and p38 while promoting phosphorylation of JNK and IκB. Leptin reconciled cardiomyocyte dysfunction, O2- yield, p47phox upregulation, STAT3 dephosphorylation and stress signaling in ob/ob mice although its action on stress signaling cascades were lost at old age. High fat diet-induced and db/db obesity displayed aging-associated cardiomyocyte anomalies reminiscent of ob/ob model albeit lost leptin response. CONCLUSIONS: Our data suggest disparate age-associated obesity response in cardiac remodeling and contractile dysfunction due to phosphorylation of Akt, eNOS and stress signaling-related oxidative stress.

Central 5-HTR2C in the Control of Metabolic Homeostasis.

The 5-hydroxytryptamine 2C receptor (5-HTR2C) is a class G protein-coupled receptor (GPCR) enriched in the hypothalamus and the brain stem, where it has been shown to regulate energy homeostasis, including feeding and glucose metabolism. Accordingly, 5-HTR2C has been the target of several anti-obesity drugs, though the associated side effects greatly curbed their clinical applications. Dissecting the specific neural circuits of 5-HTR2C-expressing neurons and the detailed molecular pathways of 5-HTR2C signaling in metabolic regulation will help to develop better therapeutic strategies towards metabolic disorders. In this review, we introduced the regulatory role of 5-HTR2C in feeding behavior and glucose metabolism, with particular focus on the molecular pathways, neural network, and its interaction with other metabolic hormones, such as leptin, ghrelin, insulin, and estrogens. Moreover, the latest progress in the clinical research on 5-HTR2C agonists was also discussed.

Leptin and Obesity: Role and Clinical Implication.

The peptide hormone leptin regulates food intake, body mass, and reproductive function and plays a role in fetal growth, proinflammatory immune responses, angiogenesis and lipolysis. Leptin is a product of the obese (ob) gene and, following synthesis and secretion from fat cells in white adipose tissue, binds to and activates its cognate receptor, the leptin receptor (LEP-R). LEP-R distribution facilitates leptin's pleiotropic effects, playing a crucial role in regulating body mass via a negative feedback mechanism between adipose tissue and the hypothalamus. Leptin resistance is characterized by reduced satiety, over-consumption of nutrients, and increased total body mass. Often this leads to obesity, which reduces the effectiveness of using exogenous leptin as a therapeutic agent. Thus, combining leptin therapies with leptin sensitizers may help overcome such resistance and, consequently, obesity. This review examines recent data obtained from human and animal studies related to leptin, its role in obesity, and its usefulness in obesity treatment.

The Inflammatory Profile of Obesity and the Role on Pulmonary Bacterial and Viral Infections.

Obesity is a globally increasing health problem, entailing diverse comorbidities such as infectious diseases. An obese weight status has marked effects on lung function that can be attributed to mechanical dysfunctions. Moreover, the alterations of adipocyte-derived signal mediators strongly influence the regulation of inflammation, resulting in chronic low-grade inflammation. Our review summarizes the known effects regarding pulmonary bacterial and viral infections. For this, we discuss model systems that allow mechanistic investigation of the interplay between obesity and lung infections. Overall, obesity gives rise to a higher susceptibility to infectious pathogens, but the pathogenetic process is not clearly defined. Whereas, viral infections often show a more severe course in obese patients, the same patients seem to have a survival benefit during bacterial infections. In particular, we summarize the main mechanical impairments in the pulmonary tract caused by obesity. Moreover, we outline the main secretory changes within the expanded adipose tissue mass, resulting in chronic low-grade inflammation. Finally, we connect these altered host factors to the influence of obesity on the development of lung infection by summarizing observations from clinical and experimental data.

Restriction of food intake by PPP1R17-expressing neurons in the DMH.

Leptin-deficient ob/ob mice eat voraciously, and their food intake is markedly reduced by leptin treatment. In order to identify potentially novel sites of leptin action, we used PhosphoTRAP to molecularly profile leptin-responsive neurons in the hypothalamus and brainstem. In addition to identifying several known leptin responsive populations, we found that neurons in the dorsomedial hypothalamus (DMH) of ob/ob mice expressing protein phosphatase 1 regulatory subunit 17 (PPP1R17) constitutively express cFos and that this is suppressed by leptin treatment. Because ob mice are hyperphagic, we hypothesized that activating PPP1R17 neurons would increase food intake. However, chemogenetic activation of PPP1R17 neurons decreased food intake and body weight of ob/ob mice while inhibition of PPP1R17 neurons increased them. Similarly, in a scheduled feeding protocol that elicits increased consumption, mice also ate more when PPP1R17 neurons were inhibited and ate less when they were activated. Finally, we found that pair-feeding of ob mice reduced cFos expression to a similar extent as leptin and that reducing the amount of food available during scheduled feeding in DMHPpp1r17 neurons also decreased cFos in DMHPpp1r17 neurons. Finally, these neurons do not express the leptin receptor, suggesting that the effect of leptin on these neurons is indirect and secondary to reduced food intake. In aggregate, these results show that PPP1R17 neurons in the DMH are activated by increased food intake and in turn restrict intake to limit overconsumption, suggesting that they function to constrain binges of eating.

Leptin and inflammatory factors play a synergistic role in the regulation of reproduction in male mice through hypothalamic kisspeptin-mediated energy balance.

BACKGROUND: Energy balance is closely related to reproductive function, wherein hypothalamic kisspeptin mediates regulation of the energy balance. However, the central mechanism of kisspeptin in the regulation of male reproductive function under different energy balance states is unclear. Here, high-fat diet (HFD) and exercise were used to change the energy balance to explore the role of leptin and inflammation in the regulation of kisspeptin and the hypothalamic-pituitary-testis (HPT) axis. METHODS: Four-week-old male C57BL/6 J mice were randomly assigned to a normal control group (n = 16) or an HFD (n = 49) group. After 10 weeks of HFD feeding, obese mice were randomly divided into obesity control (n = 16), obesity moderate-load exercise (n = 16), or obesity high-load exercise (n = 17) groups. The obesity moderate-load exercise and obesity high-load exercise groups performed exercise (swimming) for 120 min/day and 120 min × 2 times/day (6 h interval), 5 days/week for 8 weeks, respectively. RESULTS: Compared to the mice in the normal group, in obese mice, the mRNA and protein expression of the leptin receptor, kiss, interleukin-10 (IL-10), and gonadotropin-releasing hormone (GnRH) decreased in the hypothalamus; serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels and sperm quality decreased; and serum leptin, estradiol, and tumor necrosis factor-α (TNF-α) levels and sperm apoptosis increased. Moderate- and high-load exercise effectively reduced body fat and serum leptin levels but had the opposite effects on the hypothalamus and serum IL-10 and TNF-α levels. Moderate-load exercise had anti-inflammatory effects accompanied by increased mRNA and protein expression of kiss and GnRH in the hypothalamus and increased serum FSH, LH, and testosterone levels and improved sperm quality. High-load exercise also promoted inflammation, with no significant effect on the mRNA and protein expression of kiss and GnRH in the hypothalamus, serum sex hormone level, or sperm quality. Moderate-load exercise improved leptin resistance and inflammation and reduced the inhibition of kisspeptin and the HPT axis in obese mice. The inflammatory response induced by high-load exercise may counteract the positive effect of improving leptin resistance on kisspeptin and HPT. CONCLUSION: During changes in energy balance, leptin and inflammation jointly regulate kisspeptin expression on the HPT axis.

The Importance of Leptin to Reproduction.

A healthy nutritional state is required for all aspects of reproduction and is signaled by the adipokine leptin. Leptin acts in a relatively narrow concentration range: too much or too little will compromise fertility. The leptin signal timing is important to prepubertal development in both sexes. In the brain, leptin acts on ventral premammillary neurons which signal kisspeptin (Kiss1) neurons to stimulate gonadotropin releasing hormone (GnRH) neurons. Suppression of Kiss1 neurons occurs when agouti-related peptide neurons are activated by reduced leptin, because leptin normally suppresses these orexigenic neurons. In the pituitary, leptin stimulates production of GnRH receptors (GnRHRs) and follicle-stimulating hormone at midcycle, by activating pathways that derepress actions of the messenger ribonucleic acid translational regulatory protein Musashi. In females, rising estrogen stimulates a rise in serum leptin, which peaks at midcycle, synchronizing with nocturnal luteinizing hormone pulses. The normal range of serum leptin levels (10-20 ng/mL) along with gonadotropins and growth factors promote ovarian granulosa and theca cell functions and oocyte maturation. In males, the prepubertal rise in leptin promotes testicular development. However, a decline in leptin levels in prepubertal boys reflects inhibition of leptin secretion by rising androgens. In adult males, leptin levels are 10% to 50% of those in females, and high leptin inhibits testicular function. The obesity epidemic has elucidated leptin resistance pathways, with too much leptin in either sex leading to infertility. Under conditions of balanced nutrition, however, the secretion of leptin is timed and regulated within a narrow level range that optimizes its trophic effects.

Aerobic Exercise Training Exerts Beneficial Effects Upon Oxidative Metabolism and Non-Enzymatic Antioxidant Defense in the Liver of Leptin Deficiency Mice.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common forms of liver disease, which is associated with several etiological factors, including stress and dysfunction in oxidative metabolism. However, studies showed that aerobic exercise training (AET) can combat the oxidative stress (OS) and improves mitochondrial functionality in the NAFLD. To test the hypothesis that AET improves oxidative metabolism and antioxidant defense in the liver of ob/ob mice. Male ob/ob mice with eight weeks old were separated into two groups: the sedentary group (S), n=7, and the trained group (T), n=7. The T mice were submitted to an 8-week protocol of AET at 60% of the maximum velocity achieved in the running capacity test. Before AET, no difference was observed in running test between the groups (S=10.4 ± 0.7 min vs. T= 13 ± 0.47 min). However, after AET, the running capacity was increased in the T group (12.8 ± 0.87 min) compared to the S group (7.2 ± 0.63 min). In skeletal muscle, the T group (26.91 ± 1.12 U/mg of protein) showed higher citrate synthase activity compared with the S group (19.28 ± 0.88 U/mg of protein) (p =0.006). In the analysis of BW evolution, significant reductions were seen in the T group as of the fourth week when compared to the S group. In addition, food intake was not significant different between the groups. Significant increases were observed in the activity of enzymes citrate synthase (p=0.004) and ß-HAD (p=0.01) as well as in PGC-1α gene expression (p=0.002) in the liver of T group. The levels of TBARs and carbonyls, as well as SOD, CAT and GST were not different between the groups. However, in the nonenzymatic antioxidant system, we found that the T group had higher sulfhydryl (p = 0.02), GSH (p=0.001) and GSH/GSSG (p=0.02) activity. In conclusion, the AET improved body weight evolution and the aerobic capacity, increased the response of oxidative metabolism markers in the liver such as PGC-1α gene expression and citrate synthase and ß-HAD enzyme activities in ob/ob mice. In addition, AET improved the non-enzymatic antioxidant defense and did not change the enzymatic defense.

Leptin Upregulates the Expression of ß3-Integrin, MMP9, HB-EGF, and IL-1ß in Primary Porcine Endometrium Epithelial Cells In Vitro.

Obesity has become a global health problem. Research suggests that leptin, a hormone that responds to fat deposition, may be involved in mammalian reproduction; however, its precise role in embryo implantation is poorly understood. Here, primary porcine endometrium epithelium cells (PEECs) were cultured in vitro and used to evaluate the regulatory role of different leptin levels on ß3-integrin, MMP9, HB-EGF, and IL-1ß, which are, respectively, involved in four critical steps of embryo implantation. Results showed that only 0.01 nM leptin significantly improved ß3-integrin mRNA expression (p < 0.05). MMP9 and HB-EGF mRNA expressions were upregulated by 0.10-10.00 nM leptin (p < 0.05). The IL-1ß expression level was only increased by 10.00 nM leptin (p < 0.05). ß3-integrin, MMP9, HB-EGF, and IL-1ß mRNA and protein have a similar fluctuant response to increased leptin. Leptin's influence on ß3-integrin, MMP9, HB-EGF, and IL-1ß disappeared when the JAK2, PI(3)K, or MAPK signaling pathways were blocked, respectively. In conclusion, leptin affected porcine implantation by regulating the expression of ß3-integrin, MMP9, HB-EGF, and IL-1ß in a dose-dependent manner. The signaling pathways of JAK2, PI(3)K, and MAPK may participate in this regulatory process. These findings will contribute to further understanding the mechanisms of reproductive disorders in obesity.

Leptin mediates improvements in cognitive function following treatment with infliximab in adults with bipolar depression.

A potential role for leptin in the pathophysiology of bipolar disorder (BD) has been proposed. We recently investigated the effects of the tumor necrosis factor-alpha (TNF-α) antagonist infliximab in individuals with bipolar depression. Leptin is known to interact with the TNF-α system. Herein, we aimed to explore infliximab's effects on leptin and its relationship with brain structure and function. Sixty adults with bipolar depression were enrolled in this randomized, double-blind, 12-week clinical trial of adjunctive infliximab (n = 29) and saline control (n = 31), which were administered intravenously at weeks 0, 2, and 6. Plasma concentrations of leptin, TNF-α and soluble TNF receptors (sTNFR) 1 and 2 were assessed at weeks 0, 2, 6, and 12. We observed a significant decrease in leptin levels in infliximab-treated patients, relative to placebo. Infliximab treatment also significantly reduced TNF-α and sTNFR2, but not sTNFR1 levels. Changes in sTNR2 levels at week 6 significantly determined changes in leptin at week 12 in infliximab-, but not placebo-treated participants. Improvements in verbal memory and increases in global cortical volume were associated with reduction in leptin levels in the treatment group. Mediation analysis indicated that cognitive improvement in infliximab-treated patients was mediated by reductions in leptin levels, which in its turn were determined by decreases in sTNR2 levels. In conclusion, infliximab treatment reduced plasma leptin levels in individuals with BD, through modulation of sTNFR2. Decreases in leptin signaling were associated with an increase in global cortical volume and better performance in a verbal memory task.

Leptin and Nutrition in Gestational Diabetes.

Leptin is highly expressed in the placenta, mainly by trophoblastic cells, where it has an important autocrine trophic effect. Moreover, increased leptin levels are found in the most frequent pathology of pregnancy: gestational diabetes, where leptin may mediate the increased size of the placenta and the fetus, which becomes macrosomic. In fact, leptin mediates the increased protein synthesis, as observed in trophoblasts from gestational diabetic subjects. In addition, leptin seems to facilitate nutrients transport to the fetus in gestational diabetes by increasing the expression of the glycerol transporter aquaporin-9. The high plasma leptin levels found in gestational diabetes may be potentiated by leptin resistance at a central level, and obesity-associated inflammation plays a role in this leptin resistance. Therefore, the importance of anti-inflammatory nutrients to modify the pathology of pregnancy is clear. In fact, nutritional intervention is the first-line approach for the treatment of gestational diabetes mellitus. However, more nutritional intervention studies with nutraceuticals, such as polyphenols or polyunsaturated fatty acids, or nutritional supplementation with micronutrients or probiotics in pregnant women, are needed in order to achieve a high level of evidence. In this context, the Mediterranean diet has been recently found to reduce the risk of gestational diabetes in a multicenter randomized trial. This review will focus on the impact of maternal obesity on placental inflammation and nutrients transport, considering the mechanisms by which leptin may influence maternal and fetal health in this setting, as well as its role in pregnancy pathologies.

[Mutltifaceted biological roles of leptin]. / Rôles biologiques à multiples facettes de la leptine.

The identification of leptin allowed the discovery of a new endocrine system. This major adipokine controlling energy homeostasis is also involved in the regulation of neuroendocrine function and fertility. Unfortunately, leptin is not able to treat common obesity, which associates hyperleptinemia and resistance to the hormone. Conversely, treatment with recombinant leptin is effective in situations of leptin deficiency. Several pathophysiological situations associated with adipose tissue dysfunctions and abnormal regulation of leptin secretion are discussed in this review. The advantage of the potential use of the leptin assay in some pathophysiological conditions is proposed.

MCH Neurons Regulate Permeability of the Median Eminence Barrier.

Melanin-concentrating hormone (MCH)-expressing neurons are key regulators of energy and glucose homeostasis. Here, we demonstrate that they provide dense projections to the median eminence (ME) in close proximity to tanycytes and fenestrated vessels. Chemogenetic activation of MCH neurons as well as optogenetic stimulation of their projections in the ME enhance permeability of the ME by increasing fenestrated vascular loops and enhance leptin action in the arcuate nucleus of the hypothalamus (ARC). Unbiased phosphoRiboTrap-based assessment of cell activation upon chemogenetic MCH neuron activation reveals MCH-neuron-dependent regulation of endothelial cells. MCH neurons express the vascular endothelial growth factor A (VEGFA), and blocking VEGF-R signaling attenuates the leptin-sensitizing effect of MCH neuron activation. Our experiments reveal that MCH neurons directly regulate permeability of the ME barrier, linking the activity of energy state and sleep regulatory neurons to the regulation of hormone accessibility to the ARC.

Sirt6 in pro-opiomelanocortin neurons controls energy metabolism by modulating leptin signaling.

OBJECTIVE: Sirt6 is an essential regulator of energy metabolism in multiple peripheral tissues. However, the direct role of Sirt6 in the hypothalamus, specifically pro-opiomelanocortin (POMC) neurons, controlling energy balance has not been established. Here, we aimed to determine the role of Sirt6 in hypothalamic POMC neurons in the regulation of energy balance and the underlying mechanisms. METHODS: For overexpression studies, the hypothalamic arcuate nucleus (ARC) of diet-induced obese mice was targeted bilaterally and adenovirus was delivered by using stereotaxic apparatus. For knockout studies, the POMC neuron-specific Sirt6 knockout mice (PKO mice) were generated. Mice were fed with chow diet or high-fat diet, and body weight and food intake were monitored. Whole-body energy expenditure was determined by metabolic cages. Parameters of body composition and glucose/lipid metabolism were evaluated. RESULTS: Sirt6 overexpression in the ARC ameliorated diet-induced obesity. Conversely, selective Sirt6 ablation in POMC neurons predisposed mice to obesity and metabolic disturbances. PKO mice showed an increased fat mass and food intake, while the energy expenditure was decreased. Mechanistically, Sirt6 could modulate leptin signaling in hypothalamic POMC neurons, with Sirt6 deficiency impairing leptin-induced phosphorylation of signal transducer and activator of transcription 3. The effects of leptin on reducing food intake and body weight and leptin-stimulated lipolysis were also impaired. Moreover, Sirt6 inhibition diminished the leptin-induced depolarization of POMC neurons. CONCLUSIONS: Our results reveal a key role of Sirt6 in POMC neurons against energy imbalance, suggesting that Sirt6 is an important molecular regulator for POMC neurons to promote negative energy balance.

Protein Tyrosine Phosphatase (PTP1B): A promising Drug Target Against Life-threatening Ailments.

BACKGROUND: Protein tyrosine phosphatases are enzymes which help in the signal transduction in diabetes, obesity, cancer, liver diseases and neurodegenerative diseases. PTP1B is the main member of this enzyme from the protein extract of human placenta. In phosphate inhibitors development, significant progress has been made over the last 10 years. In early-stage clinical trials, few compounds have reached whereas in the later stage trials or registration, yet none have progressed. Many researchers investigate different ways to improve the pharmacological properties of PTP1B inhibitors. OBJECTIVE: In the present review, authors have summarized various aspects related to the involvement of PTP1B in various types of signal transduction mechanisms and its prominent role in various diseases like cancer, liver diseases and diabetes mellitus. CONCLUSION: There are still certain challenges for the selection of PTP1B as a drug target. Therefore, continuous future efforts are required to explore this target for the development of PTP inhibitors to treat the prevailing diseases associated with it.

Effect of Leptin on Odontoblastic Differentiation and Angiogenesis: An In Vivo Study.

INTRODUCTION: Leptin is secreted as a peptide hormone from adipose tissues. The aim of this study was to evaluate the effects of leptin on reparative dentin formation and angiogenesis in the pulp tissue of teeth in vivo. METHODS: Twenty-four 7-week-old male rats were anesthetized. Cavities were prepared in maxillary first molars. Pulp cappings were performed with collagen scaffold (Col) with a phosphate-buffered saline (PBS) vehicle (Col + PBS), leptin 1 µmol/L with Col (L1 + Col), or leptin 10 µmol/L with Col (L10 + Col). For the negative control group (no pulp capping), pulp capping was not performed. All cavities were sealed with resin-modified glass ionomer followed by a micro-computed tomographic scan, histologic examination, and immunohistochemical analysis. RESULTS: The volume of newly formed mineralized tissue in the leptin group was significantly (P < .01) higher than that in the control group based on micro-computed tomographic analysis. In histologic examination, hard tissue formation was rarely shown in the no pulp capping and Col + PBS groups. However, significantly (P < .01) larger amounts of newly mineralized tissue deposition were observed in the leptin groups. In immunohistochemical analysis, reparative dentin and new vessels formed in the pulp cavity of the leptin groups. Vascular endothelial growth factor, dentin sialoprotein, and dentin sialophosphoprotein were expressed around the newly formed mineralized tissue area. CONCLUSIONS: Leptin showed the ability to induce angiogenesis, odontogenic differentiation, and mineralization in exposed rat pulps. Leptin also exhibited favorable inflammatory responses in the pulp tissue. Not only osteodentin but also tubular dentin and new vessels were observed in the pulp cavity.

Leptin enhances N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced tumour growth in gastric mucosa of male Sprague-Dawley rats.

Individuals who are obese are at a greater risk of developing gastric cancer. They are however also hyperleptinaemic. Chronic leptin treatment has been shown to upregulate numerous cancer-causing genes in the stomach of male Sprague-Dawley rats. It is however unclear if leptin enhances the effect of gastric carcinogens in vivo. This study was therefore done to investigate the effect of leptin on gastric carcinogenesis in rats treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Twenty-four, 6-week old male Sprague-Dawley rats were divided equally into three groups: G1 served as age-matched controls; G2 was treated with MNNG in drinking water ad libitum (200 mg L-1); G3 was given leptin and MNNG. Rats were euthanized after 40 weeks of treatment and their stomachs were removed for histopathology, microarray, and RT-qPCR analysis. Fisher's exact test and one-way ANOVA were used to analyse the data. Fifty percent of the MNNG-treated rats developed gastric hyperplasia (p < 0.05), but there was no significant change in any carcinogenic genes. Concurrent MNNG and leptin treatment however induced hyperplasia, dysplasia, hypertrophy, and adenocarcinoma in 75% (6/8) of the rats; with upregulation of microRNAs, olfactory receptors, Hey2 (transcription factor), Tmed2 (vesicular trafficking), and Lcn11 (cell proliferation) genes. It appears that leptin enhances MNNG- induced tumour growth in stomachs of Sprague-Dawley rats and its role in gastric cancer requires further scrutiny.

Hydrogen Sulfide Inhibits Formaldehyde-Induced Senescence in HT-22 Cells via Upregulation of Leptin Signaling.

It has been previously demonstrated that hydrogen sulfide (H2S) prevents formaldehyde (FA)-induced neurotoxicity. However, the exact mechanisms underlying this protection remain to be fully elucidated. Neuronal senescence is involved in FA-induced neurotoxicity. Leptin signaling has anti-aging function. The present work was to investigate the protection of H2S against FA-induced neuronal senescence and the mediatory role of leptin signaling. FA-exposed HT-22 cells were used as the vitro model of FA-induced neuronal senescence. The senescence-associated ß-galactosidase (SA-ß-Gal) positive cell was detected by ß-galactosidase staining. The expressions of P16INK4a, P21CIP1, leptin, and lepRb (leptin receptor) were measured by western blot. The proliferation, viability, and apoptosis of cells were evaluated by Trypan blue exclusion assay, Cell Counting Kit-8 (CCK-8) assay, and Flow cytometry analysis, respectively. We found that H2S suppressed FA-induced senescence, as evidenced by the decrease in SA-ß-Gal positive cells, the downregulations of P16INK4a and P21CIP1, as well as decrease in cell growth arrest, in HT-22 cells. Also, H2S upregulated the expressions of leptin and lepRb in FA-exposed HT-22 cells. Furthermore, leptin tA (a specific inhibitor of the leptin) abolished the protective effects of H2S on FA-induced senescence and neurotoxicity (as evidenced by the increase in cell viability and the decrease in cell apoptosis) in HT-22 cells. These results indicated that H2S prevents FA-induced neuronal senescence via upregulation of leptin signaling. Our findings offer a novel insight into the mechanisms underlying the protection of H2S against FA-induced neurotoxicity. FA upregulates the expressions of P16INK4a and P21CIP1 via inhibiting leptin signaling, which in turn induces senescence in HT-22 cells; H2S downregulates the expressions of P16INK4a and P21CIP1 via reversing FA-downregulated leptin signaling, which in turn prevents FA-induced senescence in HT-22 cells.

Circulating adipokines and risk of obesity related cancers: A systematic review and meta-analysis.

BACKGROUND: Obesity can influence on carcinogenesis through alterations in adipokines and subsequent inflammatory changes. This meta-analysis was aimed to comprehensively assess the association between circulating adipokines and risk of obesity-related cancers. METHODS: Pubmed and Embase were searched up to October 2017 for observational studies investigating the relationship between adipokines and cancers. Pooled odds ratio and the corresponding 95% confidence interval was estimated through the meta-analysis using a random-effects model. Findings A total of 93 observational studies (adiponectin = 60, high molecular weight adiponectin = 9, leptin = 39, IL-6 = 16, TNF-α = 10, and resistin = 17) were included. Adiponectin was significantly associated with decreased risk of cancer (pooled OR 0.70, 95% CI 0.60-0.80; I2 = 71.9%; Pheterogeneity <0.01). Leptin was significantly associated with increased risk of cancer (1.26, 1.05-1.51; I2 = 65.7%; Pheterogeneity <0.01). For each 5 µg/ml increase in adiponectin and 5 ng/ml increase in leptin, the pooled OR was 0.88 (0.83-0.93; I2 = 80.2%; Pheterogeneity <0.01) and 1.05 (1.01-1.09; I2 = 67.9%; Pheterogeneity<0.01)), respectively. There was nonlinear dose-response association (Pnonlinearity for adiponectin = 0.01; Pnonlinearity for leptin = 0.003).IL-6 (1.09, 0.94-1.25), TNF- α (1.65, 0.99-2.74), and resistin (1.28, 0.78-2.11) was not associated with risk of cancer. By cancer site and type, highest category of adiponectin was associated with decreased risk of breast (OR 0.74, 0.60-0.91), colorectal (0.74, 0.60-0.91), and endometrial cancer (0.49, 0.34-0.72). Higher leptin was associated with increased risk of endometrial (1.88, 1.24-2.87) and kidney cancer (2.07, 1.51-2.83). CONCLUSION: Our study suggests that adiponectin and leptin may play a role in the etiology of cancer.